Postmenopausal estrogen synthesis and metabolism: Alterations caused by aromatase inhibitors used for the treatment of breast cancer

Lønning, Per Eystein; Dowsett, Mitch; Powles, T. J.

doi:10.1016/0022-4731(90)90241-j

Cited by 94 publications

(56 citation statements)

References 116 publications

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“…The major endocrine effect of formestane has been shown to be a significant reduction in plasma oestrogen levels, mainly E2; unlike AG, the drug causes no change in adrenal synthesis (Samojlik et al, 1977(Samojlik et al, , 1978Coombes et al, 1984;Dowsett et al, 1987;Lonning et al, 1990). In this study, irrespective of the dose, E2 serum levels decreased by an average of 40% from baseline values after only 15 days and remained unchanged thereafter, thus confirming the efficacy of formestane as an aromatase inhibitor.…”

Section: Tolerabilitysupporting

confidence: 71%

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Endocrinological and clinical evaluation of two doses of formestane in advanced breast cancer

et al. 1994

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Smmary Formestane is a selective inhibitor of oestrogen synthesis by aromatase enzymes and induces disease regression in breast cancer patients. This phase II randomised study was carried out to determine whether there were any differences in the effects of two different doses of formestane on oestradiol (E2) serum levels and to evaluate the corresponding clinical activity in post-menopausal patients with positive or unknown oestrogen receptor status pretreated or not for advanced disease. Furthermore, possible drug interference with adrenal steroidogenesis was assessed by measuring 17-hydroxycorticosteroid (17-OHCS) urinary levels. A total of 143 patients entered the study and were randomly assigned to receive formestane 250 mg (72 patients) Over the last 20 years. the activity and efficacy of endocrine treatments in post-menopausal patients with advanced breast cancer have been confirmed. The major aim of endocrine treatment is to reduce the oestrogenic stimulation of tumoral cell growth (Santen et al., 1990).Aromatase enzymes play a key role in oestrogen biosynthesis, which occurs not only in the ovaries, but also in peripheral tissues, where circulating androgens are converted to oestrone (El) and oestradiol (E2) by means of the process known as aromatisation. As peripheral aromatisation increases in post-menopausal women, becoming the main source of oestrogens, aromatase inhibition currently represents one of the major endocrine modalities for the treatment of post-menopausal breast cancer patients (Lonning et al., 1990;Santen, 1991; Johannessen et al., 1993).Aminoglutethimide (AG), the first-generation aromatase inhibitor, has generally been used as a second-line endocrine treatment for advanced breast cancer, achieving an overall response rate of about 20-25% (Lonning & Kvinnsland, 1988). However, its poor tolerability, and the fact that it also inhibits other adrenal enzyme systems (Dexter et al., 1967;Lipton & Santen, 1974), has stimulated the development of other selective and better tolerated aromatase inhibitors. Furthermore, the increasing use of tamoxifen (TMX) as adjuvant therapy has also prompted research in this field because aromatase inhibitors could theoretically be used as first-line endocrine therapy in breast cancer patients failing to respond to TMX.Formestane (4-hydroxyandrostenedione, 4-OHA) has been found to inhibit peripheral aromatisation, leading to a significant decrease in serum E2 and El levels of respectively 58% and 47% (Reed et al., 1990).This drug is a 'suicide inhibitor' in vitro because it not only inhibits the aromatisation reaction, but also irreversibly inactivates aromatase enzyme binding, an effect that appears to be more pronounced than when AG is used. The immediate advantage of using formestane is that patients do not need corticoid replacement during therapy, because the drug only inhibits aromatase enzymes without affecting cytochrome P450-related enzymes (Schwarzel et al., 1973). Given the fact that various doses of formestane are capable of reducing plasma oes...

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Section: Tolerabilitysupporting

confidence: 71%

“…As peripheral aromatisation increases in post-menopausal women, becoming the main source of oestrogens, aromatase inhibition currently represents one of the major endocrine modalities for the treatment of post-menopausal breast cancer patients (Lonning et al, 1990;Santen, 1991; Johannessen et al, 1993).…”

mentioning

confidence: 99%

Endocrinological and clinical evaluation of two doses of formestane in advanced breast cancer

et al. 1994

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“…1). While the aromatase enzyme may also aromatise testosterone directly to oestradiol, the fact that androstenedione levels are about fourfold higher compared with testosterone levels in postmenopausal women, and the higher affinity of the aromatase enzyme for the androstenedione substrate, contribute to making oestrone the major circulating unconjugated oestrogen in postmenopausal women (Lønning et al 1990). While oestrone sulphate exists in higher concentrations (Geisler et al 1997), this is an inactive conjugate that may act as a depot and (probably) a source of oestrogens to the tissue.…”

Section: Endocrine Rationale For Aromatase Inhibitionmentioning

confidence: 99%

“…While oestrone sulphate exists in higher concentrations (Geisler et al 1997), this is an inactive conjugate that may act as a depot and (probably) a source of oestrogens to the tissue. When considering circulating oestradiol, it has been estimated that probably half the amount is converted from circulating oestrone, while the residual is produced by direct aromatisation of testosterone (Lønning et al 1990). …”

Section: Endocrine Rationale For Aromatase Inhibitionmentioning

confidence: 99%

“…When considering the fact that the dose of drug administered (25 mg/day) is probably around 25 000 times the amount of total estrogens produced in a postmenopausal woman during therapy with such a compound (Lønning et al 1990), even minor metabolites causing modest interactions in the radioimmunoassays could influence the results. Such interactions have been confirmed with respect to exemestane (Johannessen et al 1997), and sample purification involving HPLC is always recommended for oestrogen assessment in patients during treatment with such steroidal compounds.…”

Section: Endocrine Studiesmentioning

confidence: 99%

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Aromatase inhibitors in breast cancer.

Lønning¹

2004

Endocr Relat Cancer

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The development of aromatase inhibitors for breast cancer therapy is a result of successful translational research exploring the biochemical effects of different compounds in vivo. Studies assessing plasma oestrogen levels as well as in vivo aromatase inhibition have revealed a consistent difference with respect to biochemical efficacy between the third generation compounds (anastrozole, letrozole and exemestane) and the previous, first and second generation drugs, corresponding to the improved clinical effects of these compounds as outlined in large phase III studies. Thus, endocrine evaluation has been found to be a valid surrogate parameter for clinical efficacy. Moreover, the results from these studies have added important biological information to our understanding of endocrine regulation of breast cancer. Based on the clinical results so far, aromatase inhibitors are believed to play a key role in future adjuvant therapy of postmenopausal breast cancer patients and potentially also for breast cancer prevention. Interesting findings such as the lack of cross-resistance between steroidal and non-steroidal compounds should be further explored, as this may add additional information to our understanding of breast cancer biology.

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Oestrogen sulphatase activity in hormone‐dependent and hormone‐independent breast‐cancer cells: Modulation by steroidal and non‐steroidal therapeutic agents

Purohit

Reed

1992

Intl Journal of Cancer

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Oestrogen sulphatase may play an important role in providing intracellular oestrogens from E1S for the growth and maintenance of breast tumours. In this study, we characterized oestrogen sulphatase in the hormone-dependent (ER/PR+) MCF-7 and in the hormone-independent (ER/PR-) MDA-MB-231 breast-cancer cells and, furthermore, examined its modulation by MPA, 4-OH-A4, tamoxifen, danazol, ethinyloestradiol and DHAS in both these cell types. Our detailed study of oestrogen sulphatase activity as a function of incubation time, E1S concentration and numbers of MCF-7 and MDA-MB-231 cells showed that more E1S was hydrolysed by MDA-MB-231 cells than by MCF-7 cells at all time points and all substrate concentrations. Additionally, although the Km values of E1S for oestrogen sulphatase in both MCF-7 and MDA-MB-231 cells were similar, the Vmax values, and therefore the activity, differed greatly. The effect of various steroidal and non-steroidal compounds also suggested differences in these 2 cell lines with respect to oestrogen sulphatase inhibition or stimulation. MPA significantly increased the hydrolysis of [3H]E1S in both cell lines, possibly through its effect on membrane fluidity. Tamoxifen increased E1S hydrolysis in MDA-MB-231 cells but not in MCF-7 cells, whereas 4-OH-A4 inhibited E1S in MCF-7 cells but not in MDA-MB-231 cells. Danazol (an isoxazol derivative of 17 alpha-ethinyltestosterone), 17 alpha-ethinyloestradiol and DHAS all significantly inhibited oestrogen sulphatase activity in both cell lines. Furthermore, danazol had a growth-inhibitory effect on both MCF-7 and MDA-MB-231 cells, although MCF-7 cells appeared to be more sensitive to growth inhibition by danazol.

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Postmenopausal estrogen synthesis and metabolism: Alterations caused by aromatase inhibitors used for the treatment of breast cancer

Cited by 94 publications

References 116 publications

Endocrinological and clinical evaluation of two doses of formestane in advanced breast cancer

Endocrinological and clinical evaluation of two doses of formestane in advanced breast cancer

Aromatase inhibitors in breast cancer.

Oestrogen sulphatase activity in hormone‐dependent and hormone‐independent breast‐cancer cells: Modulation by steroidal and non‐steroidal therapeutic agents

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